Lupus: First Partially Cure Oral Drug Enters Phase 2 Clinical Trial

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Lupus is an autoimmune disease for which there is currently no specific treatment. Modern medicines focus primarily on relieving symptoms and limiting the damage caused by the disease. Numerous studies are aimed at improving therapeutic outcomes by developing molecules with complex immunosuppressive effects. However, the latter are still limited in terms of effectiveness and especially harmlessness, especially since lupus is a very heterogeneous disease. Targeting the signaling pathway of TLR7 and 8 proteins (promoting systemic lupus erythematosus) is one of the most promising avenues. US pharmaceutical company Bristol-Myers Squibb (BMS) has recently developed a new molecule that interferes with this pathway, both preventing the symptoms of the disease and reversing the organ damage it causes. The new compound can be administered orally and is currently in Phase 2 clinical trials.

Like any autoimmune disease, lupus occurs when a person’s immune system starts attacking healthy tissues. Natural defense mechanisms are destroyed, violating “self-knowledge”. In lupus, the immune system attacks healthy tissues throughout the body, causing patients to suffer from skin rashes, extreme fatigue, severe pain, widespread inflammation, and deterioration of organs such as the kidneys and heart, which can lead to death in the long term. and in the most severe cases.

A few years ago, researchers discovered that the self-unrecognition caused by lupus involves so-called Toll-Like receptors 7 and 8 (TLRs 7 and 8). These are cytokines that are expressed, in particular, on the surface of B cells and activate the immune system when bound to viral RNA. In the case of lupus, they view patients’ RNA as a threat. The gene encoding TLR7 is located on the X chromosome, which explains the greater predisposition of women to the disease, where TLR7 is expressed twice.

Current treatments are based on blocking the interferon receptor (a protein activated during viral infection) or reducing B-lymphocyte activity caused by inhibition of the TLR7 and 8 pathways. Other treatments recommend steroids and other immunosuppressants, antimalarial drugs, anticoagulants, and anti-inflammatory drugs. . However, most of these drugs must be given by injection or infusion and can cause serious side effects. For example, taking steroids can cause weight gain, loss of bone density, increased risk of infection, etc.

“Genetic data and evaluations of injectable therapies have shown that TLRs 7 and 8 may be drug targets for the treatment of lupus,” said Alaric Dyckman, author of the new study, which will be presented at the next conference of the American Chemical Society (ACS), in a statement. “What was missing was the ability to directly block these receptors with small molecules that could be taken orally,” he explains.

Two actions together

To develop their new compound, the BMS researchers modified a molecule that blocks TLR7 and 8 signaling to reduce interaction with other molecules, increase efficiency, and allow for oral administration. The new molecule, called afimetoran, effectively binds to TLRs and blocks interferons in a phase 1 trial. It also inhibits B-cell overactivation and limits damage typical of the disease by attenuating the production of pro-inflammatory cytokines.

“With afimetoran, we could not only prevent the mice from developing lupus-like symptoms before the onset of the disease, but we could also reverse the symptoms and prevent the death of animals that died from the disease within days or weeks,” Dyckman says.

Thus, the effects of the new drug are combined with those of two other compounds already approved by the FDA. Researchers believe that this 2-in-1 action will allow for better control of disease progression, and this is when administered orally. In addition, afimetoran may be given with other medications such as corticosteroids. Therefore, they can be taken at lower doses, which limits side effects.

Although preliminary trials appear promising, the researchers believe it is too early to comment on the effectiveness of the new molecule in humans because the disease is very heterogeneous. This may work for some people and not at all for others. “Lupus is such a heterogeneous disease that it is unlikely that one approach will bring relief to all patients,” Dykman notes.

However, the results show that this approach can be used to treat other autoimmune diseases.

American Chemical Society.

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